Chronic wounds are deficient in the normal mechanisms that regulate healing, and dysregulation of these signaling pathways leads to skin breakdown and poor wound healing. Most new wound treatments have not targeted this underlying biochemistry, but have instead focused on treating infection and debridement. The renin angiotensin system (RAS) is active in connective tissue and skin and has a known role in wound healing. Effects of RAS dysregulation, including thinning epidermis, collagen degeneration, dermal layer fracture, and subcutaneous fat atrophy, are consistent with changes seen in aging skin, predisposing older adults to developing chronic wounds. This vulnerability is compounded by co-morbidities, such as diabetes, which also cause RAS dysfunction. We seek to develop small molecule drug leads that address the biology of chronic wounds. Our preliminary data established that a common oral hypertension medication restored healing in animal models with diabetic ulcers when reformulated for topical administration in the wound site, an effort that was funded by an R21 grant from the National Institute on Aging (1R21-AG43284-01). In Specific Aim 1, we will screen a larger set of RAS- effecting drugs to identify a single lead candidate for focused preclinical development. We will establish a pipeline for wound healing drug lead development by screening compounds in tissue culture for effects on RAS-driven extracellular matrix remodeling and cell migration. In Specific Aim 2, two lead compounds will be selected based on tissue culture results and will be carried forward into an animal study in an aged, diabetic porcine model. The effects of topical drug treatment on wounds will be evaluated visually throughout the study and by histology, PCR, and skin strength measurements at study conclusion. Successful completion of these aims will achieve two objectives: (1) we will identify the lead compound for topical treatment of diabetic ulcers to carry into investigational new drug (IND)-enabling studies in Phase 2, and (2) we will establish a verified process by which we can screen compounds and down-select lead candidates for drug development to address chronic wound healing. This effort will transition directly into Phase 2, in which we will formulate the lead for IND-enabling studies, assess toxicity and pharmacokinetics, develop chemistry and manufacturing controls procedures to support clinical trials, and develop a regulatory strategy for IND approval and clinical trials.